Personalized or Precision Medicine in the Dietary Approach to Obesity (PI21/01677)

The main objective of this project is to apply a precision medicine approach to try to explain the intra-individual variability of the response to different weight loss approaches: a balanced hypocaloric diet in macronutrients (MedDiet), a very low carbohydrate diet (KetoDiet) and an intermittent fasting (IF) approach, and try to establish in a personalized manner with the individual variability in genetics, metabolites, intestinal microbiome, and environmental factors the best dietary strategy for weight loss. As secondary objectives the investigators pretend to O1: To analyze whether individual variability in genetics, epigenetics, intestinal microbiome, and environmental factors determine the changes in insulin resistance, blood pressure, lipid levels and NASH markers after three different dietary interventions. O2: To analyze whether individual variability in genetics, epigenetics, intestinal microbiome, and environmental factors determine the changes in the body composition and the different ratio of free-fat/ fat mass loss after three different dietary interventions. O3: To determine the most effective intervention to increase the loss of fat mass, preserve the free-fat mass and trigger a better metabolic profile. O4: To follow-up changes in gut microbiota and DNA methylation after each of the cross-over dietary interventions. O5: To evaluate the transcriptional response of adipose tissue and elucidate its predictive value for the body-composition changes in patients subjected to the different dietary interventions. O6: To evaluate the influence of D-ß-hydroxybutyrate as well as other short-chain acyl-CoA precursor metabolites in human adipocytes lipolysis by in vitro experimentation and elucidate the influence of metabolite-sensitive histone modifications in the shaping of adipose transcriptional program and lipolysis sensitivity. O7: To develop a machine learning algorithm based on genetics, epigenetics, intestinal microbiome, and environmental factors for the prediction of the best dietary approach for weight loss in a personalized manner. To try to respond to these objectives, the investigators will apply two models: a randomized cross-over study testing three different dietary weight-loss interventions: MedDiet, KetoDiet, and IF with wash-out periods before each intervention.

The main objective of this project is to apply a precision medicine approach to try to explain the intra-individual variability of the response to different weight loss approaches: a balanced hypocaloric diet in macronutrients (MedDiet), a very low carbohydrate diet (KetoDiet) and an intermittent fasting (IF) approach, and try to establish in a personalized manner with the individual variability in genetics, metabolites, intestinal microbiome, and environmental factors the best dietary strategy for weight loss. As secondary objectives the investigators pretend to O1: To analyze whether individual variability in genetics, epigenetics, intestinal microbiome, and environmental factors determine the changes in insulin resistance, blood pressure, lipid levels and NASH markers after three different dietary interventions. O2: To analyze whether individual variability in genetics, epigenetics, intestinal microbiome, and environmental factors determine the changes in the body composition and the different ratio of free-fat/ fat mass loss after three different dietary interventions. O3: To determine the most effective intervention to increase the loss of fat mass, preserve the free-fat mass and trigger a better metabolic profile. O4: To follow-up changes in gut microbiota and DNA methylation after each of the cross-over dietary interventions. O5: To evaluate the transcriptional response of adipose tissue and elucidate its predictive value for the body-composition changes in patients subjected to the different dietary interventions. O6: To evaluate the influence of D-ß-hydroxybutyrate as well as other short-chain acyl-CoA precursor metabolites in human adipocytes lipolysis by in vitro experimentation and elucidate the influence of metabolite-sensitive histone modifications in the shaping of adipose transcriptional program and lipolysis sensitivity. O7: To develop a machine learning algorithm based on genetics, epigenetics, intestinal microbiome, and environmental factors for the prediction of the best dietary approach for weight loss in a personalized manner. To try to respond to these objectives, the investigators will apply two models: a randomized cross-over study testing three different dietary weight-loss interventions: MedDiet, KetoDiet, and IF with wash-out periods before each intervention in patients with obesity; and a second cellular approach with adipose tissue from the patients as well as with commercial cells.

Mediterranean diet based on olive oil as main fat and regular consumption of vegetables (2 daily rations), fruits (3 daily rations), legumes (3 weekly rations), fish (3 weekly rations), with low consumption of red meat and meat products (less than twice a week), dairy foods (less than once a week) and no sweets, pastries or sugary drinks. Diet will produce a 600 kcal per day caloric deficit, according to the Harris-Benedict equation for each subject. Diet will include 45% carbohydrates, 35% fat, 20% protein distributed in at least 4 meals (breakfast, lunch, afternoon snack and dinner).

Diet will produce a 600 kcal per day caloric deficit, according to the Harris-Benedict equation for each subject. Diet will include 5 % carbohydrates, 65% fat and 30% high biological value protein

In this diet subjects alternate norm caloric diet during 24 h (according to Harris-Benedict equation) and a diet including only 25% of caloric requirements the following 24 h (this day diet will include 5 % carbohydrates, 65% fat and 30% high biological value protein).

Changes in body composition and in the ratio of free-fat / fat mass loss after the three different dietary interventions.

Trailmaking Test (A - B) allows evaluating visual search speed, working memory, motor skills, visual-spatial sequencing, sustained attention, divided attention and mental flexibility (time: reduction in seconds)

Letters and numbers from the WAISspan for working memory, concentration, auditory sequencing and executive attention. (time: reduction in seconds)

Trailmaking Test (A - B) allows evaluating visual search speed, working memory, motor skills, visual-spatial sequencing, sustained attention, divided attention and mental flexibility (time: reduction in seconds) Stroop: Measures selective attention and inhibitory control. (increasing scores) Letters and numbers from the WAISspan for working memory, concentration, auditory sequencing and executive attention. (time: reduction in seconds) UPPS-P: Impulse BehaviorScale (Cyders et al. 2007; validated in Spanish by Candido et al, 2012). Self- administered scale that evaluates impulsivity. Scale of items using a 4-point likert scale (min 59 /max 136 points).

Inclusion Criteria: Participants aged ≥ 18 and <70 years old who were derived to the obesity-management unit of the Endocrinology and Nutrition Unit of the Virgen de la Victoria Hospital (Málaga). BMI between 35 and 45 kg/m2. Exclusion Criteria: Pregnant or lactating Following a prescribed diet for any reason in the past 3 months Celiac disease, Crohn's disease or any condition altering nutritional requirements. Allergies or food intolerances, as well as antibiotics treatment or usual probiotics intake.